Cul-catalyzed tandem intramolecular amidation using gem-dibromovinyl systems

Article abstract of DOI:10.1021/ol052840u

Imidazoindolones are present as the key structural motif in the family of antifungals, fumiquinazolines, and the antagonist asperlicin. The first example of a Cul-catalyzed tandem intramolecular amidation forming substituted imidazoindolones from readily

Full text of DOI:10.1021/ol052840u

ORGANIC
LETTERS
2006
Vol. 8, No. 4
653-656
CuI-Catalyzed Tandem Intramolecular
Amidation Using gem-Dibromovinyl
Systems
Josephine Yuen, Yuan-Qing Fang, and Mark Lautens*
DaVenport Chemistry Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received November 23, 2005
ABSTRACT
Imidazoindolones are present as the key structural motif in the family of antifungals, fumiquinazolines, and the antagonist asperlicin. The first
example of a CuI-catalyzed tandem intramolecular amidation forming substituted imidazoindolones from readily accessible ortho gem-
dibromovinylanilines is described.
The imidazoindolone structural motif appears in the core
structures of several biologically active molecules, including
the potent cholecystokinin antagonist asperlicin 31 and the
antifungal fumiquinazolines2 4 (Figure 1). Such 2-amino-
involving a challenging mercuration reaction of the pre-
formed indole structure.
In the context of developing a selective tandem coupling
of readily accessible gem-dihalovinyl systems5 (Scheme 1),
Scheme 1
we envisaged a double amidation reaction to access substi-
tuted imidazoindolones, and we report the results herein.
Figure 1.
(1) (a) Goetz, M. A.; Lopez, M.; Monaghan, R. L.; Chang, R. S. L.;
Lotti, V. J.; Chen, T. B. J. Antibiot. 1985, 36, 1633. (b) Liesch, J. M.;
Hensens, O. D.; Springer, J. P.; Chang, R. S. L.; Lotti, V. J. J. Antibiot.
1985, 36, 1638. (c) Sun, H. H.; Byard, S. J.; Cooper, R. J. Antibiot. 1994,
47, 599.
(2) Wong, S. M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum, A.
M.; Cooper, R. J. Antibiot. 1993, 46, 545.
substituted indole moieties are difficult to access through
traditional synthetic methods such as Fischer indole synthesis.
To address this problem, Snider used a Pd-catalyzed in-
tramolecular C-N coupling of a 2-iodoindole with a tethered
carbamate3 as part of his total synthesis of asperlicin 3.4 His
approach utilized a multistep synthesis of the iodosubstrate
(3) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417.
10.1021/ol052840u CCC: $33.50
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C(aryl)-N bond formation6 has been extensively re-
searched within the past decade due to the importance of
these compounds in diverse fields such as natural products,7
photography,8 and materials.9 The original amination (Ull-
man)10 and amidation reactions (Goldberg)11 suffered from
harsh conditions, in particular high temperatures, but due to
the pioneering work of Buchwald and co-workers6b,12 and
Hartwig,13 the mild transition-metal-catalyzed C(aryl)-N
coupling reaction is an extremely powerful tool in organic
synthesis. Buchwald and co-workers developed a catalytic
copper/diamine-ligand-based system14 enabling coupling of
a broad range of aryl and alkyl amides to aryl and heteroaryl
halides.15 They demonstrated the wider tolerance of Cu
compared to Pd and also showed that the Goldberg reaction
could be performed at room temperature. However, the scope
of the Goldberg reaction has not been extensively explored
and only recently has this reaction been extended to include
an intramolecular vinylation of amides generating lactams.16
Our previous studies showed that gem-dihalovinylanilines
can undergo a Pd-catalyzed tandem C-N/Suzuki-Miyaura
coupling.5 Herein, we describe an extension to this concept
whereby the gem-dibromovinyl moiety 1 performs an
intramolecular amidation, followed by a sequential C-N
coupling with the tethered carbamate generating imidazoin-
dolones 2 (Scheme 1). This is the first report of a one-pot
synthesis of imidazoindolones from the readily accessible
gem-dibromovinyl compound 1.17
Scheme 2
was unsuccessful in producing the desired product 2a but
gave the corresponding 2-bromoindole in moderate yield.
However, Buchwald’s combination of CuI and diamine
ligand 11 (Figure 2) successfully gave 2a in moderate yield
and 34% ee.
Figure 2.
Initial studies focused on the selection of a diamine ligand
for the formation of 2a. Screening a range of diamine ligands
(Figure 2) revealed that all six ligands gave the desired
product, although racemic trans-1,2-cyclohexyldiamine 7 was
found to be superior, followed closely by N,N-dimethyleth-
ylenediamine 11. Use of chiral trans-1,2-cyclohexyldiamine
did not significantly change the yield or ee. N-(n-butyl)-
ethylenediamine 9 and N,N,N′-trimethylethylenediamine 12
resulted in the poorest yields.
Toluene was found to be the best solvent for this reaction.
Dioxane gave a much lower yield, while DMF failed to give
any product, returning mainly starting material and a mixture
of very polar compounds. Screening a range of bases (K2-
CO3, K3PO4, Cs2CO3, and DABCO) revealed that K2CO3
gave the highest yield. The weaker organic base, DABCO,
failed to promote the reaction.
Substrate 1a was prepared as a single enantiomer by an
amide coupling of the gem-dibromovinylaniline 5 with Cbz-
L-alanine. Our initial attempt at the tandem C-N bond
formation (Scheme 2) using Pd/phosphine18 based systems
(4) (a) Snider, B. B.; Zeng, H. Org. Lett. 2002, 4, 1087. (b) Snider, B.
B.; Zeng, H. Org. Lett. 2000, 2, 4103. (c) Snider, B. B.; Zeng, H. J. Org.
Chem. 2003, 68, 545.
(5) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549.
(6) For reviews on Pd-catalyzed C-N coupling, see: (a) Littke, A. F.;
Fu, G. F. Angew. Chem., Int. Ed. 2002, 41, 4176. (b) Yang, B. H.; Buchwald,
S. L. J. Organomet. Chem. 1999, 576, 125. (c) Prim, D.; Campagne, J. M.;
Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041. For reviews on
Cu-catalyzed C-N coupling, see: (d) Scholz, U.; Ganzer, D. Synlett 2003,
15, 2428. (e) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400.
(7) Buckingham, J. Dictionary of Natural Products 1; University Press:
Cambridge, MA, 1994.
(8) Loutfy, R. O.; Hsiao, C. K.; Kazmaier, P. M. Photogr. Sci. Eng.
1983, 27, 5.
(9) D’Aprano, G.; Leclerc, M.; Zotti, G.; Schiavon, G. Chem. Mater.
1995, 7, 33.
The greatest effect on yield and ee was observed by simply
changing the ratio and quantity of ligand, CuI, and base
(Table 1). By reducing the amount of copper/ligand/base to
5 mol %, 10 mol %, and 2 equiv, respectively, the yield
increased to 73% (85% ee, Table 1, entry 2). Reducing the
amount of copper and ligand further to 2.5 mol % and 5
mol %, respectively, was equally effective (entry 3). Further
decreases gave somewhat lower yields but improved ee in
the product (entry 5). An excess of the diamine ligand is
necessary to prevent multiple ligation of the amide to copper
(entry 2 vs entry 4).14a Increasing the scale of the reaction
to 1 mmol gave 84% of the desired product (entry 6).
The scope of the reaction was initially investigated by
coupling a range of amino acids 6 to the gem-dibromovin-
(10) Ullmann, F. Chem. Ber. 1903, 36, 2382.
(11) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
(12) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805.
(13) (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (b) Hartwig, J. F.
Pure Appl. Chem. 1999, 71, 1417. (c) Hartwig, J. F. Synlett 1997, 329.
(14) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 4120. (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 7727. (c) Klapars, A.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (d) Jiang, L.; Job, G.
E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667.
(15) For a selection of other recent Cu-catalyzed amidations, see: (a)
Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (b) Shen, R.; Porco, J.
A., Jr. Org. Lett. 2000, 2, 1333. (c) Han, C.; Shen, R.; Su, S.; Porco, J. A.,
Jr. Org. Lett. 2004, 6, 27.
(16) (a) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035. (b) Kozawa, Y.; Mori,
M. J. Org. Chem. 2003, 68, 3064. (c) Kozawa, Y.; Mori, M. Tetrahedron
Lett. 2002, 43, 111. (d) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem.
Soc. 2004, 126, 14475.
(17) See the Supporting Information for synthesis of the ortho gem-
dibromovinylaniline from commercially available 2-nitrobenzaldehyde.
(18) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
Org. Lett., Vol. 8, No. 4, 2006
654

Table 1. Effect of Quantity of Ligand, Base, and CuIa
Table 2. Scope of Amino Acids
CuI
(mol %)
K2CO3
(equiv)
ligand
(mol %)
time
(h)
yieldb
(%)
eee
(%)
entry
1
2
3
4
5
6
20
5
2.5
5
1
2.5
5
2
2
2
2
2
40
10
5
5
2
12
13
13
13
37
13
50c
73
73 (72c)
61
62
84d
49
85
86
96
98
86
5
a All reactions performed on a 0.26-0.52 mmol scale in toluene at 120
°C using racemic trans-1,2-cyclohexyldiamine as ligand. b HPLC yield.
c Isolated yields. d Reaction performed on a 1 mmol scale. e ee determined
using chiral HPLC.
ylaniline 5 followed by tandem C-N bond formation to
provide substituted imidazoindolones 2.
Alkyl groups were well tolerated, even the sterically
hindered isopropyl substituent (Table 2, entry 4), although
the reaction required a longer time to achieve complete
conversion (22 h). The isobutyl analogue 2e (entry 5) is
noteworthy as it forms the core structure of the antifungal
fumiquinazolines 4.4 The incorporation of heteroatoms in the
side chain is particularly useful to allow for further deriva-
tization of the ester or amine functionality (entries 6 and 7).
The amide 1g (entry 7) contains two carbamates that could
potentially react to give either the five- or nine-membered
ring or intermolecular coupling product. Only the five-
membered product 2g was observed. Both the Cbz and more
sterically hindered Boc protecting groups were tolerated.
Exploring a range of electron-donating and electron-
withdrawing groups on the aromatic ring indicated that
substituents on the aromatic ring do not seem to affect the
efficiency of the cyclization reaction, except for the case of
the 5-methoxy substituted compound 1m (Table 3, entry 6),
which gave the product in a decreased yield possibly due to
the increased steric hindrance. In some cases, a minor
byproduct observed was the 2-bromoindole with hydrolysis
of the amide bond.
In some cases, the preservation of the chiral center
originating from the amino acid remained very high with
up to 86% ee for the alanine analogue 2a, 93% for lysine
2g, and 89% for leucine 2e. Similarly, the dibenzyloxy 2i
and fluoro-substituted 2l aromatic rings both gave the product
with 89% ee. For the remaining cases, the ee value was
highly variable and the extent of epimerization may be related
to a variety of factors. Longer reaction times do not
significantly reduce the ee values. A possible rationalization
is that the 2-bromoindole intermediate is very susceptible to
epimerization because the proton at the stereocenter is much
more acidic than that in the starting material due to its ketone
character.19 The extent of epimerization of the 2-bromoindole
is related to the lifetime of this intermediate, which is
a All isolated yields. Reaction performed using CuI (2.5 mol %), racemic
trans-1,2-cyclohexyldiamine (5 mol %), and K2CO3 (2 equiv) in toluene at
120 °C for 13-24 h. b The ee of the starting material was 4%.
dependent on the rate of the second amidation step. Thus,
the more electron-rich 2-bromoindoles may experience
significant epimerization of the 2-bromoindole intermediate
due to the slower oxidative addition of the second step. The
analogues that contain electron-withdrawing groups in either
the aromatic ring or side-chain substituent possess a more
acidic stereocenter, which explains the poor ee values in cases
such as 2f. Further studies to resolve the epimerization
problem are ongoing.
The ability to access 3-substituted indoles is very attractive
due to the presence of these moieties in many alkaloids. In
the event, a higher catalyst loading (10 mol %) was required
to obtain the desired product 15 in good yield (52%) since
(19) Treatment of the starting material with either K2CO3 or 1,2-
cyclohexyldiamine did not result in any racemization. For a reference
illustrating the ketone character of an analogous N-acyl pyrrole, see: Harada,
S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005,
44, 4365.
Org. Lett., Vol. 8, No. 4, 2006
655

Scheme 3. 3-Substituted Imidazoindolones
Table 3. Scope of Aryl Substituents
substrates via a novel tandem intramolecular C-N bond
formation. This process is particularly attractive for industrial
use since copper iodide is a very cheap, air-stable compound
and can be used without purification, in contrast to the high
cost of palladium and problematic removal of Pd residues
from polar compounds. Additionally, this methodology could
provide facile access to the natural products asperlicin 3 and
fumiquinazolines 4.
Scheme 4
a All isolated yields. Reaction performed using CuI (2.5 mol %), racemic
trans-1,2-cyclohexyldiamine (5 mol %), and K2CO3 (2 equiv) in toluene at
120 °C for 12-49 h.
Acknowledgment. This work is supported by NSERC
(Canada), Merck Frosst (IRC), and the University of Toronto.
Y.-Q.F. thanks the Ontario Government and the University
of Toronto for financial support in the form of postgraduate
scholarships (OGS).
the usual conditions gave mainly monocyclized product
(40%) 14 and the desired product (28%) 15 (Scheme 3).
We attempted one “post-ring forming” reaction and found
that treatment of 2a with Adam’s catalyst successfully
removed the Cbz group with concomitant reduction of the
indole to give 16 as a single diastereoisomer (Scheme 4).
In conclusion, we have developed an efficient one-pot
procedure giving rapid access to a wide range of substituted
imidazoindolones from readily prepared gem-dibromovinyl
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052840U
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Org. Lett., Vol. 8, No. 4, 2006